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EP2799441B1 - Verfahren für die konvergente Synthese von Calicheamicin-Derivaten - Google Patents

Verfahren für die konvergente Synthese von Calicheamicin-Derivaten Download PDF

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EP2799441B1
EP2799441B1 EP14171872.6A EP14171872A EP2799441B1 EP 2799441 B1 EP2799441 B1 EP 2799441B1 EP 14171872 A EP14171872 A EP 14171872A EP 2799441 B1 EP2799441 B1 EP 2799441B1
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carbon atoms
alkyl
naphthylidene
trivalent
radical
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EP2799441A1 (de
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Justin Keith Moran
Jianxin Gu
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Wyeth LLC
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Wyeth LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • This invention describes intermediates for use in processes for the convergent synthesis of calicheamicin derivatives, and similar analogs.
  • the potent family of antibacterial and antitumor agents known collectively as the calicheamicins or the LL-E33288 complex are disclosed in U.S. Patent No. 4,970,198 (1990) .
  • the compounds contain a methyltrisulfide that can be reacted with appropriate thiols to form disulfides while at the same time introducing a functional group such as a hydrazide or similar nucleophile. Examples of this reaction with the calicheamicins are given in U.S. Patent No. 5,053,394 .
  • U.S. Patent No. 5,770,701 is directed to a process for preparing targeted forms of disulfide compounds of the LL-E33288 complex.
  • a linker 4-(4-acetyl-phenoxy)butanoic acid, is condensed with calicheamicin N-acetyl gamma dimethyl hydrazide to afford the carboxylic acid-hydrazone which is further treated with N-hydroxysuccinimide to give the OSu ester (N-succinimidyloxy) which is ready for conjugation with a chosen biomacromolecule.
  • calicheamicin derivatives are complicated by multiple calicheamicin containing synthetic steps having low overall yields.
  • the calicheamicin moiety is inherently toxic, and when already part of a synthetic target necessitates increased safety precautions which must be observed during manipulation and purification of the products of each of the synthetic steps.
  • the claimed process provides a method of fewer steps involving the calicheamicin moiety with increased yields.
  • the invention provides a compound of the formula wherein:
  • the invention further provides a compound of the formula wherein:
  • An additional process discussed includes a method of preparing antitumor antibiotics of Formula (I): wherein:
  • An additional process includes preparation of compounds of Formula (I): wherein:
  • the processes include a purifying of step comprising the use of a reverse phase high performance liquid chromatography having a mobile phase of about pH 7.0 to 9.0 followed with a normal phase chromatography.
  • the processes include:
  • the processes include but are not limited to Alk 1 is an alkylene of 2 to 5 carbon atoms, and Sp 1 is an oxygen atom.
  • Alk 1 is an alkylene of 3 carbon atoms.
  • the processes include but are not limited Z 1 is alkyl of 1 to 3 carbon atoms.
  • the processes include but are not limited Ar is 1,2-, 1,3-, or 1,4-phenylene, or 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, 2,6-, or 2,7-naphthylidene.
  • the processes include but are not limited Ar is 1,4-phenylene.
  • the processes include but are not limited Q is -NNHCO-.
  • the processes include but are not limited Sp is straight or branched-chain divalent or trivalent alkyl radical of 1 to 12 carbon atoms.
  • the processes include but are not limited Sp is straight or branched-chain divalent or trivalent alkyl radical of 1 to 6 carbon atoms.
  • the processes include but are not limited the alcohol solvent is methanol.
  • the processes include but are not limited the inert solvent is acetonitrile.
  • the processes include but are not limited alkyl carboxylic acid is acetic acid.
  • the processes include but are not limited the inert organic solvent is acetonitrile.
  • the processes include but are not limited Z is
  • alkoxy refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • thioalkoxy refers to an alkoxy group as defined, having a sulfur radical attached thereto.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone.
  • alkyl can be used alone or as part of a chemical name.
  • aryl is defined as an aromatic carbocyclic moiety and may be substituted or unsubstituted.
  • Aryl groups have 6 to 14 carbon atoms and include phenyl and napthyl.
  • aryl also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are "fused") wherein at least one of the carbocyclic rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
  • Carboxy is defined as a -CO 2 H radical.
  • halogen refers to an atom of fluorine, chlorine, bromine, or iodine.
  • heteroaryl refers to a 4 to 10 membered ring structure, which ring structure includes one to four heteroatoms.
  • a heteroaryl comprises a heterocyclic ring system of one to three fused rings, in which at least one ring may have an aromatic character and contains 1 to 4 heteroatoms the same or different selected from the group consisting of S, N, and O. The remaining rings of the ring system may be fully unsaturated, partially saturated, or fully saturated. Each ring comprises three to ten members.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen and include for example nitrogen, oxygen, sulfur, phosporus, and selenium.
  • nitro means -NO 2 .
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents of organic compounds include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • alkyl means a straight or branched alkyl of 1 to 18 carbon atoms, preferably 2 to 5 carbon atoms, 1 to 4 carbon atoms or 1 to 3 carbon atoms. In some embodiments of the invention the term alkyl is methyl.
  • alcohol solvent means methanol, ethanol and the like with a boiling point of less than about 100°C.
  • Alkylene refers to an alkyl, as defined above, which is a diradical, rather than a radical.
  • An alkylene can be branched or unbranched and can have 2-18 carbons.
  • Ambient temperature is about 25°C.
  • Inert solvent or inert organic solvent describes a solvent that will neither react or form a covalent bond in the steps to prepare compounds of Formula (I), trilinker-activated esters or trifunctional linker intermediates as described herein.
  • An example of an inert solvent or inert organic solvent may be mixtures such as but not limited to acetonitrile/ethylacetate (1:1)), dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dioxane or acetonitrile.
  • An inert solvent may contain 0-50% N,N-dimethylformamide.
  • An inert organic solvent is for example acetonitrile, ethyl acetate or dichloromethane.
  • An organic base is for example an alkylamine base which includes triethylamine, N,N-diethylmethylamine, N,N-diethylaniline, N,N-diethylethylenediamine, N,N-diisopropylethylamine, tributylamine or tripropylamine and further include dimethylaminopyridine(DMAP) with diisopropylethylamine (DIEA), N-methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4-methylpyridine or pyridine.
  • a base is an alkali metal hydroxide, alkali metal carbonate or alkali metal bicarbonate.
  • Bilinker-carboxylic acid 3 is reacted with N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or other carbodiimide or N,N'-disuccinimdyl carbonate in an inert solvent such as dichloromethane, tetrahydrofuran, dioxane, or acetonitrile containing 0-50% DMF or DMF to generate trilinker-activated ester 4 where Z is selected from the group consisting of
  • reaction of bilinker-carboxylic acid 3 with a coupling agent such as 1,3-dicyclohexylcarbodiimide(DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • a coupling agent such as 1,3-dicyclohexylcarbodiimide(DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • N-hydroxysuccinimide or other comparable carboxyl-activating group in an inert solvent such as N,N-dimethylformamide (DMF), tetrahydrofuran, dioxane or acetonitrile
  • N-hydroxysuccinimide DCC at ambient temperature in dioxane.
  • a preferred solvent mixture is acetonitrile containing 0-50% DMF.
  • the trilinker-activated ester 4 can be isolated by removal of the volatile solvents and further purified by
  • Trilinker-activated ester 4 is first reacted with an alkali metal carbonate which includes but is not limited to sodium carbonate and forms the sodium salt of trilinker-activated ester 4 in acetonitrile by heating at gentle reflux. Further reaction of the sodium salt of trilinker-activated ester 4 with methyltrithioantitumor antibiotic 5 at about -15°C in an inert organic solvent, preferably acetonitrile gives activated ester 6 wherein Z, Alk 1 , Sp 1 , Ar, Z 1 , Q, Sp and W' are hereinbefore defined. In particular, N-acetyl-LL-E33288 ⁇ 1 ' is the preferred methyltrithioantitumor antibiotic 5. Preferred is the reaction in acetonitrile at about 0°C.
  • an organic base may replace the alkali metal carbonate which preferably includes triethylamine, in acetonitrile at about 0°C.
  • reaction of bilinker-carboxylic 3 prepared by condensation of carboxylic acid 1 wherein Alk 1 , Sp 1 , Ar and Z 1 are hereinbefore defined, with mercapto compound 2 according to scheme I, is reacted with methyltrithioantitumor antibiotic 5 in the presence of triethylamine in N,N-dimethylformamide (DMF) at about -5°C affords intermediate 7 which is further converted to trilinker-activated ester 6 by reaction with N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or other carbodiimide or N,N'-disuccinimdyl
  • reaction mixture is concentrated in vacuo to a residue which is partitioned between ethyl acetate and water.
  • the separated organic layer is washed with water, saturated sodium chloride and dried (MgSO 4 ).
  • the organic layer is evaporated in vacuo to give an oily residue which crystallized from ethyl acetate-hexane affording 0.21 g of the title compound as a colorless solid.
  • reaction mixture is filtered and the ethyl acetate evaporated to a residue which is dissolved in 10 ml of ethyl acetate and applied to a column of 110 g of silica gel.
  • the column is eluted with 1-5% methyl alcohol in ethyl acetate to give 0.322 g of the desired product having 65.27% purity as determined by HPLC.

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Claims (20)

  1. Verbindung der Formel
    Figure imgb0084
     worin:
    Alk1 eine verzweigte oder unverzweigte Alkylenkette mit 2 bis 6 Kohlenstoffatomen ist;
    Sp1 ausgewählt ist aus -S-, -O-, -CONH-, -NHCO- und -NR'-; Z1 H oder Alkyl mit 1 bis 5 Kohlenstoffatomen ist;
    Ar 1,2-, 1,3- oder 1,4-Phenylen ist, gegebenenfalls substituiert mit einer, zwei oder drei Gruppe(n),
    unabhängig ausgewählt aus Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 5 Kohlenstoffatomen, Thioalkoxy mit 1 bis 4 Kohlenstoffatomen, Halogen, Nitro, -COOR', -CONHR', -O(CH2)nCOOR', -S(CH2)nCOOR', -O(CH2)nCONHR' und -S(CH2)nCONHR' oder ein 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, 2,6- oder 2,7-Naphthyliden, gegebenenfalls substituiert mit einer, zwei oder drei oder vier Gruppe(n),
    unabhängig ausgewählt aus Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 5 Kohlenstoffatomen, Thioalkoxy mit 1 bis 4 Kohlenstoffatomen, Halogen, Nitro, -COOR', -CONHR', -O(CH2)nCOOR' , -S(CH2)nCOOR' , -O(CH2)nCONHR' und -S(CH2)nCONHR' ;
    n eine ganze Zahl von 0 bis 5 ist;
    R' ein geradkettiges oder verzweigtes Alkyl mit 1 bis 5 Kohlenstoffatomen ist, gegebenenfalls substituiert mit einer oder zwei Gruppe (n) von -OH, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Thioalkoxy mit 1 bis 4 Kohlenstoffatomen;
    Sp ein geradkettiger oder verzweigtkettiger bivalenter oder trivalenter Alkylrest mit 1 bis 18 Kohlenstoffatomen,
    bivalenter oder trivalenter Aryl- oder Heteroarylrest, bivalentes oder trivalentes Cycloalkyl mit 3 bis 18 Kohlenstoffatomen oder Heterocycloalkylrest, bivalenter oder trivalenter Aryl- oder Heteroaryl-alkyl(C1-C18)-Rest,
    bivalenter oder trivalenter Cycloalkyl- oder Heterocyclo-alkyl-alkyl (C1-C18) -Rest oder bivalenter oder trivalenter ungesättigter Alkylrest mit 2 bis 18 Kohlenstoffatomen ist, wobei Heteroaryl Furyl, Thienyl, N-Methylpyrrolyl, Pyridinyl, N-Methylimidazolyl, Oxazolyl, Pyrimidinyl, Chinolyl, Isochinolyl, N-Methylcarbazoyl, Aminocoumarinyl oder Phenazinyl ist, und wobei, wenn Sp ein trivalenter Rest ist,
    kann es zusätzlich substituiert sein durch Dialkylamino mit 1 bis 5 Kohlenstoffatomen, Alkoxy mit 1 bis 5 Kohlenstoffatomen, Hydroxy oder Alkylthio mit 1 bis 5 Kohlenstoffatomgruppen;
    Q ausgewählt ist aus der Gruppe, bestehend aus -NNHCO-, -NNHCS- und -NNHCONH-;
    Z ausgewählt ist aus der Gruppe, bestehend aus
    Figure imgb0085
    Figure imgb0086
  2. Verbindung nach Anspruch 1, worin Z
    Figure imgb0087
     ist.
  3. Verbindung nach Anspruch 1, worin Alk1 eine verzweigte oder unverzweigte Alkylenkette mit 3 Kohlenstoffatomen ist.
  4. Verbindung nach Anspruch 1, worin Z1 Alkyl mit 1 bis 3 Kohlenstoffatomen ist.
  5. Verbindung nach Anspruch 1, worin Ar ausgewählt ist aus der Gruppe, bestehend aus 1,2-Phenylen, 1,3-Phenylen, 1,4-Phenylen, 1,2-Naphthyliden, 1,3-Naphthyliden, 1,4-Naphthyliden, 1,5-Naphthyliden, 1,6-Naphthyliden, 1,7-Naphthyliden, 1,8-Naphthyliden, 2,3-Naphthyliden, 2,6-Naphthyliden und 2,7-Naphthyliden.
  6. Verbindung nach Anspruch 1, worin Ar 1,4-Phenylen ist.
  7. Verbindung nach Anspruch 1, worin Q -NNHCO- ist.
  8. Verbindung nach Anspruch 1, worin Sp ein geradkettiger oder verzweigtkettiger bivalenter oder trivalenter Alkylrest mit 1 bis 12 Kohlenstoffatomen ist.
  9. Verbindung nach Anspruch 1, worin Sp ein geradkettiger oder verzweigtkettiger bivalenter oder trivalenter Alkylrest mit 1 bis 6 Kohlenstoffatomen ist.
  10. Verbindung nach Anspruch 1, welche Buttersäure, 3-Mercapto-3-methyl-, 2-[(E)-1-[4-[4-[(2,5-Dioxo-1-pyrrolidinyl)oxy]-4-oxobutoxy]phenyl]ethyliden]hydrazid ist.
  11. Natriumsalz der Verbindung nach Anspruch 1.
  12. Verbindung der Formel
    Figure imgb0088
     worin:
    Alk1 eine verzweigte oder unverzweigte Alkylenkette mit 2 bis 6 Kohlenstoffatomen ist;
    Sp1 ausgewählt ist aus -S-, -O-, -CONH-, -NHCO- und -NR'-; Z1 H oder Alkyl mit 1 bis 5 Kohlenstoffatomen ist;
    Ar 1,2-, 1,3- oder 1,4-Phenylen ist, gegebenenfalls substituiert mit einer, zwei oder drei Gruppe(n),
    unabhängig ausgewählt aus Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 5 Kohlenstoffatomen, Thioalkoxy mit 1 bis 4 Kohlenstoffatomen, Halogen, Nitro, -COOR', -CONHR', - O(CH2)nCOOR', -S(CH2)nCOOR', -O(CH2)nCONHR' und -S(CH2)nCONHR' oder ein 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, 2,6- oder 2,7-Naphthyliden, gegebenenfalls substituiert mit einer, zwei oder drei oder vier Gruppe(n),
    unabhängig ausgewählt aus Alkyl mit 1 bis 6 Kohlenstoffatomen, Alkoxy mit 1 bis 5 Kohlenstoffatomen, Thioalkoxy mit 1 bis 4 Kohlenstoffatomen, Halogen, Nitro, -COOR', -CONHR', -O(CH2)nCOOR' , -S(CH2)nCOOR' , -O(CH2)nCONHR' und -S(CH2)nCONHR' ;
    n eine ganze Zahl von 0 bis 5 ist;
    R' ein geradkettiges oder verzweigtes Alkyl mit 1 bis 5 Kohlenstoffatomen ist, gegebenenfalls substituiert mit einer oder zwei Gruppen von -OH, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Thioalkoxy mit 1 bis 4 Kohlenstoffatomen;
    Sp ein geradkettiger oder verzweigtkettiger bivalenter oder trivalenter Alkylrest mit 1 bis 18 Kohlenstoffatomen, bivalenter oder trivalenter Aryl- oder Heteroarylrest, bivalenter oder trivalenter Cycloalkylrest mit 3 bis 18 Kohlenstoffatomen oder Heterocycloalkylrest, bivalenter oder trivalenter Aryl- oder Heteroaryl-alkyl(C1-C18)-Rest, bivalenter oder trivalenter Cycloalkyl- oder Heterocyclo-alkyl-alkyl(C1-C18)-Rest oder bivalenter oder trivalenter ungesättigter Alkylrest mit 2 bis 18 Kohlenstoffatomen ist, wobei Heteroaryl Furyl, Thienyl, N-Methylpyrrolyl, Pyridinyl, N-Methylimidazolyl, Oxazolyl, Pyrimidinyl, Chinolyl, Isochinolyl, N-Methylcarbazoyl, Aminocoumarinyl oder Phenazinyl ist, und wobei, wenn Sp ein trivalenter Rest ist, kann es zusätzlich substituiert sein durch Dialkylamino mit 1 bis 5 Kohlenstoffatomen, Alkoxy mit 1 bis 5 Kohlenstoffatomen, Hydroxy oder Alkylthio mit 1 bis 5 Kohlenstoffatomgruppen und
    Q ausgewählt ist aus der Gruppe, bestehend aus -NNHCO-, -NNHCS- und -NNHCONH-.
  13. Verbindung nach Anspruch 12, worin Alk1 eine verzweigte oder unverzweigte Alkylenkette mit 3 Kohlenstoffatomen ist.
  14. Verbindung nach Anspruch 12, worin Z1 Alkyl mit 1 bis 3 Kohlenstoffatomen ist.
  15. Verbindung nach Anspruch 12, worin Ar ausgewählt ist aus der Gruppe, bestehend aus 1,2-Phenylen, 1,3-Phenylen, 1,4-Phenylen, 1,2-Naphthyliden, 1,3-Naphthyliden, 1,4-Naphthyliden, 1,5-Naphthyliden, 1,6-Naphthyliden, 1,7-Naphthyliden, 1,8-Naphthyliden, 2,3-Naphthyliden, 2,6-Naphthyliden und 2,7-Naphthyliden.
  16. Verbindung nach Anspruch 12, worin Ar 1,4-Phenylen ist.
  17. Verbindung nach Anspruch 12, worin Q -NNHCO- ist.
  18. Verbindung nach Anspruch 12, worin Sp ein geradkettiger oder verzweigtkettiger bivalenter oder trivalenter Alkylrest mit 1 bis 12 Kohlenstoffatomen ist.
  19. Verbindung nach Anspruch 12, worin Sp ein geradkettiger oder verzweigtkettiger bivalenter oder trivalenter Alkylrest mit 1 bis 6 Kohlenstoffatomen ist.
  20. Verbindung nach Anspruch 12, welche Buttersäure, 3-Mercapto-3-methyl-, 2-[(E)-1-[4-(4-Hydroxy-4-oxobutoxy)phenyl]ethyliden]hydrazid ist.
EP14171872.6A 2006-02-21 2007-02-16 Verfahren für die konvergente Synthese von Calicheamicin-Derivaten Active EP2799441B1 (de)

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WO2011080739A2 (en) 2009-12-29 2011-07-07 Yeda Research And Development Co. Ltd. Synergistic antibiotic combinations and derivatives
MY167579A (en) * 2012-08-16 2018-09-20 Pfizer Glycoconjugation processes and compositions
EP3065780A1 (de) 2013-11-04 2016-09-14 Pfizer Inc. Anti-efna4-antikörper-arzneimittelkonjugate
ES2768611T3 (es) * 2013-11-04 2020-06-23 Pfizer Intermedios y procedimientos para sintetizar derivados de calicheamicina
AU2015253422B2 (en) 2014-04-30 2020-09-03 Abbvie Stemcentrx Llc Anti-PTK7 antibody-drug conjugates
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WO2019018647A1 (en) 2017-07-20 2019-01-24 Pfizer Inc. ANTI-GD3 ANTIBODIES AND CONJUGATES ANTIBODY-MEDICATION
EP3720842A4 (de) * 2017-12-06 2021-11-03 Ontario Institute For Cancer Research Acylhydrazon-linker, verfahren und verwendungen davon
US11850287B2 (en) 2017-12-22 2023-12-26 Ontario Institute For Cancer Search (Oicr) Heterocyclic acyl hydrazone linkers, methods and uses thereof
CN111647865B (zh) * 2020-08-06 2020-11-24 北京卓立汉光仪器有限公司 溅射镀膜方法、装置及系统

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EP2799441A1 (de) 2014-11-05
US8273862B2 (en) 2012-09-25
JP2009527557A (ja) 2009-07-30
JP2014196352A (ja) 2014-10-16
AU2007217795B2 (en) 2012-09-13
IL193343A (en) 2017-03-30
US20130018179A1 (en) 2013-01-17
KR20080094925A (ko) 2008-10-27
HK1203515A1 (en) 2015-10-30
SI2799441T1 (en) 2018-07-31
KR101454489B1 (ko) 2014-10-27
EP1987048A2 (de) 2008-11-05
PT2799441T (pt) 2018-05-29
DK2799441T3 (en) 2018-05-28
WO2007098124A2 (en) 2007-08-30
JP5179383B2 (ja) 2013-04-10
RU2436790C2 (ru) 2011-12-20
CN101389639B (zh) 2012-07-18
PL2799441T3 (pl) 2018-08-31
US9802890B2 (en) 2017-10-31
AU2007217795A1 (en) 2007-08-30
CA2642194C (en) 2015-12-08
US10343989B2 (en) 2019-07-09
SI1987048T1 (sl) 2015-01-30
CN101389639A (zh) 2009-03-18
TW200806685A (en) 2008-02-01
JP2016011316A (ja) 2016-01-21
EP1987048B1 (de) 2014-11-19
US8546549B2 (en) 2013-10-01
WO2007098124A3 (en) 2007-12-27
CR10230A (es) 2008-10-03
NO20083698L (no) 2008-11-12
RU2008132777A (ru) 2010-03-27
MX2008010768A (es) 2008-11-28
DK1987048T3 (en) 2014-12-15
CY1120206T1 (el) 2018-12-12
IL193343A0 (en) 2009-08-03
GT200800161A (es) 2009-01-15
US20140081010A1 (en) 2014-03-20
US20090312530A1 (en) 2009-12-17
BRPI0708149A2 (pt) 2011-05-17
HUE037880T2 (hu) 2018-09-28
PT1987048E (pt) 2015-01-14
AR059592A1 (es) 2008-04-16
ES2527107T3 (es) 2015-01-20
BRPI0708149B1 (pt) 2022-01-25
US20180016228A1 (en) 2018-01-18
ECSP088691A (es) 2008-09-29
US20150315138A1 (en) 2015-11-05
SG170013A1 (en) 2011-04-29
ES2670709T3 (es) 2018-05-31
US20070197455A1 (en) 2007-08-23
PE20071229A1 (es) 2007-11-30
CL2009001487A1 (es) 2009-10-16
TR201808220T4 (tr) 2018-07-23
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